Our long-term goal is to understand the mechanisms by which lipids regulate gene expression in physiology and disease. A principal mechanism whereby modified iipids influence the function of cells of the artery wall is through activation of members of the nuclear receptor superfamily. PPAR8 is a nuclear receptor activated by native and oxidized polyunsaturated fatty acids whose role in mammalian physiology remains obscure. Preliminary data indicate that PPARdelta is expressed in endothelial cells and smooth muscle cells and is strongly induced during the differentiation of monocytes to macrophages. Recent work has also shown that synthetic ligands for PPARdelta induce expression of the putative cholesterol/phospholipid transporter ABCA1 and raise HDL levels in primates. These studies suggest that PPARdelta is an important modulator of the reverse cholesterol transport pathway. This proposal is focused on defining the role of the nuclear receptor PPARdelta in lipid metabolism and atherosclerosis. The first aim is to define the role of PPARdelta in regulating gene expression in macrophages and other peripheral cells. Since PPARdelta is widely expressed, it has the potential to regulate gene expression in many different cell types, including those that also express PPARalpha or PPARgamma. Macrophages and adipose tissue express both PPARgamma and PPARdelta8 however, it is not yet clear whether there is functional overlap between these receptors. While many PPARgamma target genes are known in macrophages, it is not known whether these are also targets of PPARdelta or whether there are PPARdelta selective targets. Preliminary data presented below indicates that ABCA1 is a PPARdelta selective target in human macrophages. The second aim is to characterize gene expression and lipid metabolism in genetically defined macrophages that lack PPARdelta. The importance of PPARdelta in regulating gene expression, lipid uptake, cholesterol efflux and cytokine production will be tested. We will also endeavor to determine whether there is functional overlap between the PPARdelta and PPARgamma pathways. The third aim is to analyze the role of PPARdelta in macrophage function and atherogenesis in vivo. First, PPARdelta null mice will be crossed to the LDLR-/- and apoE-/- mice to determine the impact of ubiquitous PPARdelta expression on reverse cholesterol transport and atherogenesis. Second, transgenic mice will be created that express multiple copies of the PPARdelta locus.